1. LIVER BIOCHEMISTRY

2. LIVER STRUCTURE sinusoids central vein portal vein bile canaliculi
hepatic artery
bile duct
sinusoids
bile canaliculi
central vein

3. LIVER FUNCTIONS Distribution of nutrients
All types of metabolism (protein, lipid, carbohydrate, vitamin, mineral)
Excretory (bile acids, urea synthesis)
Destruction of toxic substances
Depot of iron, vitamins

4. METABOLISM OF CARBS IN LIVER
glycolisis
metabolism of fructose and galactose
gluconeogenesis
release of glucose into blood (maintain the stable glucose concentration in blood)
conversion of pyruvate into acetyl CoA
tricarboxylic acid cycle
pentose phosphate pathway
glycogenolysis, glycogenogenesis

5. METABOLISM OF LIPIDS IN LIVER
synthesis of lipoproteins
synthesis of triacylglyserols
synthesis of phospholipids
synthesis of fatty acids, elongation of fatty acids chain, desaturation
synthesis of cholesterol
ketone bodies formation
lipolysis
fatty acids oxidation

6. METABOLISM OF PROTEINS IN LIVER
protein synthesis, including blood plasma proteins
protein decomposition; urea synthesis
conversion of proteins into carbs and lipids
interconversion of aminoacids
conversion of proteins into low molecular weight nitrogen containing substances

7. Vitamin metabolism in liver
Formation of active form of vitamin D
Formation of vitamin A from carotins
Depo of cyanocobalamine and folic acid
Depo of vitamin E
Phosphorilation of vitamins B, formation of coenzyme forms

8. DETOXIFICATION OF TOXIC SUBSTANCES IN LIVER
Phase I and phase II.
Phase I:
hydrolysis,
reduction,
oxidation.
These reactions introduce functional group (—OH, —NH2, —SH, or —COOH) and usually result in a little increase of hydrophylic properties

9. Phase II includes:
glucuronation,
sulfation,
acetylation,
methylation,
conjugation with glutathione,
conjugation with aminoacids (glycin, taurin, glutamic acid)
Phase II results in the marked increase of hydrophylic properties of xenobiotic.

10. General ways of xenobiotics biotransformation and their localization in cell
REACTION
ENZYME
LOCALIZATION
PHASE I
Hydrolysis
Reduction
Oxidation
Esterase
Peptidase Epoxide hydrolase
Azo- and nitro-reduction
Carbonyl reduction
Disulfide reduction
Sulfoxide reduction
Alcohol dehydrogenase
Aldehyde dehydrogenase
Aldehyde oxidase
Xanthine oxidase
Monoamine oxidase
Diamine oxidase
Flavin-monooxygenases
Cytochrome P450
Microsomes, cytosol, lysosomes, blood lysosomes Microsomes, cytosol
Microflora, microsomes, cytosol
Cytosol, blood, microsomes
Cytosol
Mitochondria, cytosol
Mitochondria
Microsomes
PHASE II
Glucuronide conjugation
Sulfate conjugation
Glutathione conjugation
Amino acid conjugation
Acetylation
Methylation
Cytosol, microsomes
Mitochondria, microsomes
Cytosol, microsomes, blood

11. PHASE I Hydrolysis Reduction
Esterases (carboxyesterases, cholinesterases, phosphatases)
Peptidases
Reduction
Metals and xenobiotics containing aldehyde, keto, disulfide, alkyn, azo, or nitro group are often reduced
Reducing agents:
Reduced glutathione,
FADH2,
FMN,
NADH
NADPH.

12. Alcohol dehydrogenase
Oxidation
Alcohol dehydrogenase

13. Aldehyde dehydrogenase Xanthine dehydrogenase-Xanthine oxidase
Oxidizes aldehydes to carbonic acids
Xanthine dehydrogenase-Xanthine oxidase
Monoaminooxidase
Oxidative deamination of amines (serotonin) and many xenobiotics

14. Cytochrom P450
The highest concentration – in endoplasmic reticulum of hepatocytes (microsomes).
Hem containing protein.
Catalyzes monooxigenation of oxygen atom into substrate; another oxygen atom is reduced to water
Electrons are transferred from NADPH to cytochrome P450 through flavoprotein NADPH-cytochrome P450 reductase.

15. SCHEME OF MONOOXYGENASE SYSTEM

16. SCHEME OF MONOOXYGENASE SYSTEM IN ENDOPLASMIC RETICULUM

18. The example of reaction that is catalyzed by cytochrome P450: hydroxylation of aliphatic carbon

19. The example of reaction that is catalyzed by cytochrome P450: hydroxylation of aromatic carbon

20. Examples of reactions catalyzed by cytochrome P450: heteroatom oxygenation

21. Examples of reactions catalyzed by cytochrome P450: oxidative group transfer

22. JAUNDICES

23. NORMAL METABOLISM OF BILE PIGMENTS
CELLS OF RES
Indirect bilirubin
NADP+
NADPH2
Biliverdin reductase
Biliverdin
Iron
Globin
Verdoglobin
Hemoxi-genase
Hemoglobin
ERYTHROCYTES
KIDNEYS
Stercobilinogen
URINE
Stercobilin
Indirect bilirubin 1,7-20,5 mkmol/l
albumin
UDP-glucoronil-transferase
Direct bilirubin mkmol/l
BLOOD
LIVER
Bilirubin mono-glucoronid, 20 %
Bilirubin di-glucoronid, 80 %
Dipyrols
-glucoro-nidase
Glucoronic acid
Direct bilirubin
BILE
INTESTINE
Mesobilirubin
Mesobilirubin (urobilinogen)
STOOL

24. Bilirubin di-glucoronid

25. HEMOLYTIC (PREHEPATIC) JAUNDICE
Jaundice due to the excessive breakdown of red blood cells.
Causes:
sickle cell anemia,
malaria,
thalassemia,
autoimmune disorders,
massive hemorrhage

26. METABOLISM OF BILE PIGMENTS IN HEMOLYTIC JAUNDICE
CELLS OF RES
Indirect bilirubin
albumin
Biliverdin reductase
UDP-glucoronil-transferase
Direct bilirubin
NADP+
NADPH2
Biliverdin
Iron
Globin
Verdoglobin
Hemoglobin
Hemoxi- genase
BLOOD
LIVER
Bilirubin mono-glucoronid, 20 %
Bilirubin diglucoronid, 80 %
-glucoro- nidase
Glucoronic acid
BILE
ERYTHROCYTES
KIDNEYS
INTESTINE
STOOL
Stool hypercholic
URINE
Urine dark
Mesobilirubin
Mesobilinogen (urobilinogen)
Stercobilinogen
Stercobilin
Urobilin

27. PARENCHYMAL (HEPATIC) JAUNDICE
occurs due to the liver disease and inability of liver to metabolize and remove bilirubin from the biliary system
Causes:
cirrhosis,
cancer,
viral hepatitis,
Gilbert’s syndrome, toxins or drugs, etc.

28. METABOLISM OF BILE PIGMENTS IN HEPATIC JAUNDICE
CELLS OF RES
Indirect bilirubin
albumin
Biliverdin reductase
UDP-glucoronil-transferase
Direct bilirubin
NADP+
NADPH2
Biliverdin
Iron
Globin
Verdoglobin
Hemoglobin
Hemoxi- genase
BLOOD
LIVER
Bilirubin mono-glucoronid, 20 %
Bilirubin diglucoronid, 80 %
-glucoro- nidase
Glucoronic acid
BILE
ERYTHROCYTES
KIDNEYS
Urobilinogen
INTESTINE
STOOL
Stool hypocholic
URINE
Urine dark
Stercobi-linogen
Stercobilin
Bilirubin
Urobilin
Mesobilirubin
Mesobilinogen (urobilinogen)
Stercobilinogen

29. ОBSTRUCTIVE (POST-HEPATIC)
JAUNDICE
is caused by obstruction of bile flow from the liver
Causes:
carcinoma in the bile duct or gall bladder,
presence of gallstones in the biliary system,
infection by parasites,
pancreatitis, etc.

30. METABOLISM OF BILE PIGMENTS IN OBSTRUCTIVE JAUNDICE
CELLS OF RES
Indirect bilirubin
albumin
Biliverdin reductase
UDP-glucoronil-transferase
Direct bilirubin
NADP+
NADPH2
Biliverdin
Iron
Globin
Verdoglobin
Hemoglobin
Hemoxi- genase
BLOOD
LIVER
Bilirubin mono-glucoronid, 20 %
Bilirubin diglucoronid, 80 %
Bile acids
-glucoro- nidase
Glucoronic acid
BILE
ERYTHROCYTES
KIDNEYS
INTESTINE
STOOL
Stool acholic, steatorhea
URINE
Direct bilirubin
Bile acids
Urine dark, foaming